Cancer is a class of diseases in which a group of cells exhibit uncontrolled growth, invasion and destruction of adjacent tissues, and metastasis (spread of aberrant cells spread to other locations in the body), or in which cells fail to undergo programmed cell death (e.g. apoptosis) at the appropriate time. Cancer causes about 13% of all deaths worldwide and according to the American Cancer Society, 7.6 million people died from cancer in the world during 2007. Current treatment for cancer depends upon the specific type of cancer and tissue involved, but includes surgery, chemotherapy, radiation therapy, immunotherapy, and monoclonal antibody therapy among other methods. Although these treatment methods have been successful in some cases, they are hindered by adverse side effects or limited efficacy. For example, the efficacy of eliminating cancerous tissue by surgical removal of tumors is often limited by the tendency of cancers to invade adjacent tissue and metastasize to other sites in the body. Chemotherapy, as well as radiation treatment, is often limited by toxicity or damage to other tissues in the body. Thus, cancer remains a major health concern and there is a need for improved methods of treating cancer.
Inflammation is strongly correlated to cancer initiation, progression and metastasis (Mantovani et al. (2008) Nature, Vol. 454: 436-444). Pro-inflammatory mediators such as prostaglandins, cytokines, reactive oxygen/nitrogen species, and growth factors, activate PI3K/Akt signaling that increases pro-survival, proliferative, and metastatic processes (Dillon et al. (2007) Oncogene, Vol. 26: 1338-1345; Qiao et al. (2008) Cell Cycle, Vol. 7: 2991-2996; Prueitt et al. (2007) International Journal of Cancer, Vol. 120: 796-805; Wang and DuBois (2006) Gut, Vol. 55: 115-122). Mutations in the PI3K/Akt pathway are common in human tumors, which result in unregulated PI3K/Akt signaling (Carnero et al. (2008) Curr Cancer Drug Targets, Vol. 8: 187-98; Dillon et al., 2007; Yuan and Cantley (2008) Oncogene, Vol. 27: 5497-5510). Thus, pharmacological control of the PI3K/Akt signaling axis is an aim for cancer therapeutics.
Akt kinase activity is directly regulated by the tumor suppressor protein phosphatase 2A (PP2A), which functions to dephosphorylate Akt at threonine 308 and serine 473 (Andjelkovic et al. (1996) Proc. Natl. Acad. Sci., Vol. 93: 5699-5704; Resjö et al. (2002) Cellular Signalling, Vol. 14: 231-238). However, PP2A activity is commonly decreased in human cancers (Chen et al. (2004) Cancer Cell, Vol. 5: 127-136). One mechanism by which PP2A activity is suppressed in cancer is by the formation of complexes with endogenous protein inhibitors such as CIP2A and I2PP2A (Junttila et al. (2007) Cell, Vol. 130: 51-62; Li et al. (1996) J. Biol. Chem., Vol. 271: 11059-11062). I2PP2A, which is also known as SET, is a potent inhibitor of PP2A and has been implicated in AML and blast crisis CML (Li et al., 1996; Neviani et al. (2005) Cancer Cell, Vol. 8: 355-368). Despite the endogenous inhibition in many human cancers, PP2A activity can be pharmacologically increased and is a potential molecular target for cancer therapeutics (Guichard et al. (2006) Carcinogenesis, Vol. 27: 1812-1827; Perrotti and Neviani (2008) Cancer and Metastasis Reviews, Vol. 27: 159-168; Switzer et al. (2009) Oncogene, Vol. 28: 3837-3846).
ApoE-derived peptides have shown promising effects in abating injury in inflammation-associated neuropathologies, such as Alzheimer's disease, multiple sclerosis and traumatic brain injury (Hoane et al. (2009) Journal of Neurotrauma, Vol. 26: 121-129; Li et al. (2006) J Pharmacol Exp Ther, Vol. 318: 956-965; Wang et al. (2007) Neuroscience, Vol. 144: 1324-33; WO 2006/029028; WO 2003/026479). Inflammation is a common feature of both neurological diseases and cancer, and PI3K/Akt signaling is also unregulated in neurodegenerative diseases such as Alzheimer's (Griffin et al. (2005) J Neurochem, Vol. 93: 105-17; Pei et al. (2003) Acta Neuropathol, Vol. 105: 381-92). Also, the expression of PP2A subunits is decreased in Alzheimer's patients, which is consistent with increased tau hyper-phosphorylation observed in this pathology (Vogelsberg-Ragaglia et al. (2001) Experimental Neurology, Vol. 168: 402-412). ApoE peptides have also been reported to increase PP2A activity by relieving inhibition by SET (see, e.g., WO 2008/080082). Thus, ApoE peptides represent a viable therapeutic approach for treating various conditions, including cancer, inflammatory conditions, and neurodegenerative diseases.
Although several ApoE peptides have proven to be effective in treating specific conditions, there is a need in the art to develop new ApoE-derived peptides with increased potency and greater safety windows. In particular, it is desirable to develop new ApoE-based peptide therapeutics that can effectively treat multiple conditions.